Berylliosis

Template:Infobox medical condition (new) Berylliosis, or chronic beryllium disease (CBD), is a chronic allergic-type lung response and chronic lung disease caused by exposure to beryllium and its compounds, a form of beryllium poisoning. It is distinct from acute beryllium poisoning, which became rare following occupational exposure limits established around 1950.<ref name=OSHAhealtheffects/> Berylliosis is an occupational lung disease.

While there is no cure, symptoms can be treated.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Signs and symptoms

With single or prolonged exposure by inhalation the lungs may become sensitized to beryllium. Berylliosis has a slow onset and progression. Some people who are sensitized to beryllium may not have symptoms.<ref name=OSHAhealtheffects>OSHA Beryllium Health Effects Page accessed March 29, 2016</ref> Continued exposure causes the development of small inflammatory nodules, called granulomas.<ref>Template:Cite journal</ref> Of note, the authors of a 2006 study suggested that beryllium inhalation was not the only form of exposure and perhaps skin exposure was also a cause, as they found that a reduction in beryllium inhalation did not result in a reduction in chronic beryllium disease or beryllium sensitization.<ref>Template:Cite journal</ref>

Granuloma formation is seen in other diseases such as tuberculosis and sarcoidosis. Sarcoidosis, like berylliosis, also produces granulomas without a necrotic core, and so distinction between the two processes can be difficult.

Ultimately, this process leads to restrictive lung disease (a decrease in diffusion capacity).

The earliest symptoms are typically cough and shortness of breath.<ref name="Fishman">Template:Cite book</ref> Other symptoms include chest pain, joint aches, weight loss, and fever.

Rarely, one can get granulomas in other organs including the liver.

The onset of symptoms can range from weeks up to tens of years from the initial exposure. In some individuals, a single exposure to beryllium can cause berylliosis.

Pathogenesis

In susceptible persons, beryllium exposure can lead to a cell-mediated immune response. The T-cells become sensitized to beryllium. Each subsequent exposure leads to an immune response involving CD4+ helper T-lymphocytes and macrophages accumulating in the lungs. As this response continues macrophages, CD4+ T-lymphocytes and plasma cells aggregate together to form the noncaseating granulomas.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> When beryllium is phagocytized by macrophages, the beryllium triggers macrophage apoptosis, thereby reducing beryllium clearance from the lungs and eventually resulting in secondary necrosis and lysis.<ref>Template:Cite journal</ref> Eventually, the outcome is fibrosis of the lung.<ref>Template:Cite journal</ref><ref name=ATSDRmanagement>Agency for Toxic Substances and Disease Registry via the CDC. Beryllium Toxicity: How Should Patients Exposed to Beryllium Be Treated and Managed? Page last updated: May 23, 2008</ref>

Several studies have shown that there is a genetic component to beryllium sensitivity. Specifically, those beryllium-exposed workers with a mutation at the HLA-DPB1 Glu⁶⁹ position have increased prevalence of beryllium sensitization and chronic beryllium disease.<ref name=GeneRev2011>Template:Cite journal</ref> The HLA-DPB1 gene is important for MHC class II molecule function on antigen presenting cells.<ref name=GeneRev2011/> A study of the immune response to beryllium in individuals who express the HLA-DP2 allele found that CD4 T-cells do not detect the Template:Chem2 cation itself, but instead detect surface changes in the HLA-DP2/peptide complex in which Template:Chem2 is embedded. Those researchers concluded that chronic beryllium disease is a predisposition that lies between "allergic hypersensitivity and autoimmunity."<ref name=Cell2014>Template:Cite journal</ref>

According to the International Agency for Research on Cancer, beryllium and beryllium compounds are Category 1 carcinogens; they are carcinogenic to both animals and humans.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Diagnosis

X-ray image of a 54-year-old man working in the aerospace manufacturing industry with berylliosis

The differential diagnosis for berylliosis includes:<ref>Template:Cite journal</ref>

• Sarcoidosis
• Granulomatous lung diseases
  • Tuberculosis
  • Fungal infections (e.g., histoplasmosis)
  • Granulomatosis with polyangiitis
• Idiopathic pulmonary fibrosis
• Hypersensitivity pneumonitis
• Asthma

Diagnosis of berylliosis is based on history of beryllium exposures, documented beryllium sensitivity, and granulomatous inflammation on lung biopsy. Given the invasive nature of a lung biopsy, diagnosis can also be based on clinical history consistent with berylliosis, abnormal chest x-ray or CT scan findings, and abnormalities in pulmonary function tests.<ref name=":02" />

The radiologic and pathologic features of berylliosis are very similar to sarcoidosis. Due to the strong clinical and histopathological resemblance of sarcoidosis and berylliosis, patients are sometimes misdiagnosed with sarcoidosis until the history of exposure to beryllium is elicited and beryllium hypersensitivity demonstrated with specific testing. Some studies suggest that up to 6% of all cases of sarcoidosis are actually berylliosis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

The beryllium lymphocyte proliferation test (BeLPT) is the standard way of determining sensitivity to beryllium.<ref name=":02">Template:Cite journal</ref> The test is performed by acquiring either peripheral blood or fluid from a bronchial alveolar lavage, and lymphocytes are cultured with beryllium sulfate. Cells are then counted and those with elevated number of cells are considered abnormal.<ref>Template:Cite journal</ref> Those exposed persons with two abnormal BeLPT tested with peripheral blood, or one abnormal and one borderline result, are considered beryllium sensitized. Also, those with one abnormal BeLPT tested with fluid from a bronchial alveolar lavage are considered sensitized.<ref name=":02" />

Chest radiography findings of berylliosis are non-specific. Early in the disease radiography findings are usually normal. In later stages interstitial fibrosis, pleural irregularities, hilar lymphadenopathy and ground-glass opacities have been reported.<ref>Template:Cite journal</ref><ref name=Sharma>Template:Cite journal</ref> Findings on CT are also not specific to berylliosis. Findings that are common in CT scans of people with berylliosis include parenchymal nodules in early stages. One study found that ground-glass opacities were more commonly seen on CT scan in berylliosis than in sarcoidosis. In later stages hilar lymphadenopathy, interstitial pulmonary fibrosis and pleural thickening.<ref name=Sharma />

Classification

Berylliosis is an occupational disease.<ref name=OSHAhealtheffects/> Relevant occupations are those where beryllium is mined, processed or converted into metal alloys, or where machining of metals containing beryllium and recycling of scrap alloys occurs.<ref>ATSDR. ToxGuide for Beryllium September 2002</ref> It is associated with aerospace manufacturing, microwave semiconductor electronics, beryllium mining or manufacturing of fluorescent light bulbs (which once contained beryllium compounds in their internal phosphor coating).<ref>General Electric Fluorescent Lamps TP 111R, Dec. 1978, says on pg. 23 that since 1949 GE lamps used relatively inert phosphates found to be safe in ordinary handling of either the intact or broken lamp.</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Beryllia was used in lamp manufacture because of ceramic's obvious virtues for insulation and heat resistance, and also because beryllia could be made transparent.<ref>Template:Cite book</ref> Certain welding anodes along with other electrical contacts and even non-sparking tools are made of beryllium copper alloy and the subsequent machining of such materials would cause the disease as well.

Prevention

Because it can be difficult to control industrial exposures to beryllium, it is advisable to use any methods possible to reduce airborne and surface contamination by beryllium, to minimize the use of beryllium and beryllium-containing alloys whenever possible, and to educate people about the potential hazards if they are likely to encounter beryllium dust or fumes.<ref name="Lang">Template:Cite journal</ref> It is important to damp wipe metallographic preparation equipment to prevent accumulation of dry particles. Sectioning, grinding, and polishing must be performed under sufficiently vented hoods equipped with special filters.<ref>Batich, Ray and James M. Marder. (1985) Beryllium In (Ed. 9), Metals Handbook: Metallography and Microstructures (pp. 389–391). Metals Park, Ohio: American Society for Metals.</ref>

On 29 January 2009, the Los Alamos National Laboratory announced it was notifying nearly 2,000 current and former employees and visitors that they may have been exposed to beryllium in the lab and may be at risk of disease. Concern over possible exposure to the material was first raised in November 2008, when a box containing beryllium was received at the laboratory's short-term storage facility.<ref>Template:Cite news</ref>

Treatment

There is no cure for berylliosis; the goals of treatment are to reduce symptoms and slow the progression of disease.<ref name=ATSDRmanagement/><ref name=Sood/>

Although the evidence that stopping exposure to beryllium decreases progression of the disease is limited,<ref name=Seidler/> it is still considered to be an accepted approach to treatment in any stage of disease.<ref name="Rossman 1996 945–947" />

People with early stages of disease, without lung function abnormalities or clinical symptoms, are periodically monitored with physical exams, pulmonary function testing and radiography.<ref name="Sood">Template:Cite journal</ref>

Once clinical symptoms or significant abnormalities in pulmonary function testing appear, treatments include oxygen and oral corticosteroids and whatever supportive therapy is required.<ref name=OSHAhealtheffects/><ref name=":02" /><ref name="Sood"/>

Outcomes

Overall mortality rates are 5–38%.<ref>Template:Cite journal</ref>

Epidemiology

The number of workers in the United States exposed to beryllium vary but has been estimated to be as high as 800,000 during the 1960s and 1970s.<ref>Template:Cite journal</ref> A more recent study from 2004 estimated the number of exposed workers in the United States to be around 134,000.<ref>Template:Cite journal</ref>

The rate of workers becoming sensitized to beryllium varies based on genetics and exposure levels. In one study researchers found the prevalence of beryllium sensitization to range from 9–19% depending on the industry.<ref name=Kreiss>Template:Cite journal</ref> Many workers who are found to be sensitive to beryllium also meet the diagnostic criteria for chronic beryllium disease.<ref name=Kreiss/> In one study of nuclear workers, among those who were sensitized to beryllium, 66% were found to have chronic beryllium disease as well.<ref name=Kreiss2>Template:Cite journal</ref> The rate of progression from beryllium sensitization to chronic beryllium disease has been estimated to be approximately 6–8% per year.<ref name=Seidler>Template:Cite journal</ref><ref>Template:Cite journal</ref> Stopping exposure to beryllium in those sensitized has not been definitively shown to stop the progression to chronic beryllium disease.<ref name=Seidler/>

The overall prevalence of chronic beryllium disease among workers exposed to beryllium has ranged from 1–5% depending on industry and time period of study.<ref name=Kreiss/><ref name=Kreiss2 /><ref>Template:Cite journal</ref>

The general population is unlikely to develop acute or chronic beryllium disease because ambient air levels of beryllium are normally very low (<0.03 ng/m³).<ref>Template:Cite book</ref> However, a study found 1% of people living within 3/4 of a mile of a beryllium plant in Lorain, Ohio, had berylliosis after exposure to concentrations estimated to be less than 1 milligram per cubic metre of air. In the United States the Beryllium Case Registry contained 900 records, early cases relating to extraction and fluorescent lamp manufacture, later ones coming from the aerospace, ceramics and metallurgical industries.<ref>David Geraint James, Alimuddin Zumla, The granulomatous disorders, Cambridge University Press, 1999, Template:ISBN, pages 336–337</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

History

Since the 1920s, beryllium has been used in electronics, ceramics, research and development labs, aircraft, and the atomic energy and defense industry.<ref name="Lang"/> Cases of bronchitis and pneumonia-like symptoms were reported in Germany and Russia in the 1930s among workers mining and refining beryllium. By 1946, a cluster of cases associated with fluorescent lamp manufacturers were apparent in the United States, and the lamp industry stopped using beryllium in 1949.<ref name="Rossman 1996 945–947">Template:Cite journal</ref> At that time, most construction trades and industries were unaware of the potential risks associated with beryllium exposure.<ref>Template:Cite journal</ref>

It occasionally killed early workers in nuclear weapons design, such as Herbert L. Anderson.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The physicist W. W. Hansen who was instrumental in the development of the klystron also died of the disease in 1949.

Beryllium sensitivity testing was first performed as a cutaneous beryllium patch test in the early 1950s, but was discontinued due to the test stimulating sensitization or aggravating existing chronic beryllium disease.<ref>Agency for Toxic Substances and Disease Registry. September 2002 Toxicological Profile: Beryllium. See also 2009 Addendum</ref>Template:Rp

In the 1990s, the DOE began screening employees using the BeLPT test in facilities where beryllium was used, to take preventive measures against beryllium exposure. Somewhat alarmingly, clerical staff who were never involved in handling the material had developed asymptomatic sensitivities.<ref>Template:Cite journal</ref>

External links

• ATSDR Case Studies in Environmental Medicine: Beryllium Toxicity U.S. Department of Health and Human Services
• CDC – Research on Beryllium Sensitization and Chronic Beryllium Disease – NIOSH Workplace Safety and Health Topic
• Beryllium Network
• Health-cares.net
• Instant insight from the Royal Society of Chemistry examining the molecular basis of chronic beryllium disease
• Template:Cite book